SICTIN: Rapid footprinting of massively parallel sequencing data

BACKGROUND: Massively parallel sequencing allows for genome-wide hypothesis-free investigation of for instance transcription factor binding sites or histone modifications. Although nucleotide resolution detailed information can easily be generated, biological insight often requires a more general view of patterns (footprints) over distinct genomic features such as transcription start sites, exons or repetitive regions. The construction of these footprints is however a time consuming task. METHODS: The presented software generates a binary representation of the signals enabling fast and scalable lookup. This representation allows for footprint generation in mere minutes on a desktop computer. Several different input formats are accepted, e.g. the SAM format, bed-files and the UCSC wiggle track. CONCLUSIONS: Hypothesis-free investigation of genome wide interactions allows for biological data mining at a scale never before seen. Until recently, the main focus of analysis of sequencing data has been targeted on signal patterns around transcriptional start sites which are in manageable numbers. Today, focus is shifting to a wider perspective and numerous genomic features are being studied. To this end, we provide a system allowing for fast querying in the order of hundreds of thousands of features

Active Galactic Nuclei Selection and Demographics: A New Age with JWST/MIRI

Understanding the coevolution of supermassive black holes and their host systems requires a comprehensive census of active galactic nuclei (AGNs) behavior across a wide range of redshift, luminosity, obscuration level, and galaxy properties. We report significant progress with JWST toward this goal from the Systematic Mid-infrared Instrument Legacy Extragalactic Survey (SMILES). Based on comprehensive spectral energy distribution (SED) analysis of 3273 MIRI-detected sources, we identify 217 AGN candidates over a survey area of ∼34 arcmin2, including a primary sample of 111 AGNs in normal massive galaxies (M * > 109.5 M ☉) at z ∼ 0–4, an extended sample of 86 AGN candidates in low-mass galaxies (M * < 109.5 M ☉), and a high-z sample of 20 AGN candidates at z ∼ 4–8.4. Notably, about 80% of our MIRI-selected AGN candidates are new discoveries despite the extensive pre-JWST AGN searches. Even among the massive galaxies where the previous AGN search is believed to be thorough, 34% of the MIRI AGN identifications are new, highlighting the impact of obscuration on previous selections. By combining our results with the efforts at other wavelengths, we build the most complete AGN sample to date and examine the relative performance of different selection techniques. We find the obscured AGN fraction increases from L AGN,bol ∼ 1010 L ⊙ to 1011 L ⊙ and then drops toward higher luminosity. Additionally, the obscured AGN fraction gradually increases from z ∼ 0 to z ∼ 4 with most high-z AGNs obscured. We discuss how AGN obscuration, intrinsic SED variations, galaxy contamination, survey depth, and selection techniques complicate the construction of a complete AGN sample

Short-term efficacy of physical interventions in osteoarthritic knee pain. A systematic review and meta-analysis of randomised placebo-controlled trials.

BACKGROUND: Treatment efficacy of physical agents in osteoarthritis of the knee (OAK) pain has been largely unknown, and this systematic review was aimed at assessing their short-term efficacies for pain relief. METHODS: Systematic review with meta-analysis of efficacy within 1-4 weeks and at follow up at 1-12 weeks after the end of treatment. RESULTS: 36 randomised placebo-controlled trials (RCTs) were identified with 2434 patients where 1391 patients received active treatment. 33 trials satisfied three or more out of five methodological criteria (Jadad scale). The patient sample had a mean age of 65.1 years and mean baseline pain of 62.9 mm on a 100 mm visual analogue scale (VAS). Within 4 weeks of the commencement of treatment manual acupuncture, static magnets and ultrasound therapies did not offer statistically significant short-term pain relief over placebo. Pulsed electromagnetic fields offered a small reduction in pain of 6.9 mm [95% CI: 2.2 to 11.6] (n = 487). Transcutaneous electrical nerve stimulation (TENS, including interferential currents), electro-acupuncture (EA) and low level laser therapy (LLLT) offered clinically relevant pain relieving effects of 18.8 mm [95% CI: 9.6 to 28.1] (n = 414), 21.9 mm [95% CI: 17.3 to 26.5] (n = 73) and 17.7 mm [95% CI: 8.1 to 27.3] (n = 343) on VAS respectively versus placebo control. In a subgroup analysis of trials with assumed optimal doses, short-term efficacy increased to 22.2 mm [95% CI: 18.1 to 26.3] for TENS, and 24.2 mm [95% CI: 17.3 to 31.3] for LLLT on VAS. Follow-up data up to 12 weeks were sparse, but positive effects seemed to persist for at least 4 weeks after the course of LLLT, EA and TENS treatment was stopped. CONCLUSION: TENS, EA and LLLT administered with optimal doses in an intensive 2-4 week treatment regimen, seem to offer clinically relevant short-term pain relief for OAK

AGN Selection and Demographics: A New Age with JWST/MIRI

Understanding the co-evolution of supermassive black holes (SMBHs) and their host systems requires a comprehensive census of active galactic nuclei (AGN) behavior across a wide range of redshift, luminosity, obscuration level and galaxy properties. We report significant progress with JWST towards this goal from the Systematic Mid-infrared Instrument Legacy Extragalactic Survey (SMILES). Based on comprehensive SED analysis of 3273 MIRI-detected sources, we identify 217 AGN candidates over a survey area of $\sim$34 arcmin$^2$, including a primary sample of 111 AGNs in normal massive galaxies ($M_{*}>10^{9.5}~M_\odot$) at $z\sim$0--4, an extended sample of 86 AGN {\it candidates} in low-mass galaxies ($M_{*}<10^{9.5}~M_\odot$) and a high-$z$ sample of 20 AGN {\it candidates} at $z\sim$4--8.4. Notably, about 80\% of our MIRI-selected AGN candidates are new discoveries despite the extensive pre-JWST AGN searches. Even among the massive galaxies where the previous AGN search is believed to be thorough, 34\% of the MIRI AGN identifications are new, highlighting the impact of obscuration on previous selections. By combining our results with the efforts at other wavelengths, we build the most complete AGN sample to date and examine the relative performance of different selection techniques. We find the obscured AGN fraction increases from $L_{\rm AGN, bol}\sim10^{10}~L_\odot$ to $10^{11}~L_\odot$ and then drops towards higher luminosity. Additionally, the obscured AGN fraction gradually increases from $z\sim0$ to $z\sim4$ with most high-$z$ AGNs obscured. We discuss how AGN obscuration, intrinsic SED variations, galaxy contamination, survey depth and selection techniques complicate the construction of a complete AGN sample.Comment: 32 pages, 21 figures, submitted to Ap

Behavioural signs of pain in cats: an expert consensus

To identify where a consensus can be reached between veterinary experts in feline medicine on the core signs sufficient for pain (sufficient to indicate pain when they occur, but not necessarily present in all painful conditions) and necessary for pain (necessary in the presence of pain, but not always indicative of pain). Methods A modified Delphi technique was used, consisting of four rounds of questions and evaluation using nineteen participants during the period December 2014 and May 2015. Agreement was considered to be established when 80% of the experts concurred with the same opinion. Results Twenty-five signs were considered sufficient to indicate pain, but no single sign was considered necessary for it. Discussion Further studies are needed to evaluate the validity of these 25 behavioural signs if a specific pain assessment tool is to be developed that is capable of assessing pain in cats based on observational methods alone. The signs reported here may nonetheless help both vets and owners form an initial evaluation of the pain status of cats in their care

Reduction of artefacts caused by hip implants in CT-based attenuation-corrected PET images using 2-D interpolation of a virtual sinogram on an irregular grid

Metallic prosthetic replacements, such as hip or knee implants, are known to cause strong streaking artefacts in CT images. These artefacts likely induce over- or underestimation of the activity concentration near the metallic implants when applying CT-based attenuation correction of positron emission tomography (PET) images. Since this degrades the diagnostic quality of the images, metal artefact reduction (MAR) prior to attenuation correction is required

Pathological Computed Tomography Features Associated with Adverse Outcomes after Mild Traumatic Brain Injury:A TRACK-TBI Study with External Validation in CENTER-TBI

Importance: A head computed tomography (CT) with positive results for acute intracranial hemorrhage is the gold-standard diagnostic biomarker for acute traumatic brain injury (TBI). In moderate to severe TBI (Glasgow Coma Scale [GCS] scores 3-12), some CT features have been shown to be associated with outcomes. In mild TBI (mTBI; GCS scores 13-15), distribution and co-occurrence of pathological CT features and their prognostic importance are not well understood. Objective: To identify pathological CT features associated with adverse outcomes after mTBI. Design, Setting, and Participants: The longitudinal, observational Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study enrolled patients with TBI, including those 17 years and older with GCS scores of 13 to 15 who presented to emergency departments at 18 US level 1 trauma centers between February 26, 2014, and August 8, 2018, and underwent head CT imaging within 24 hours of TBI. Evaluations of CT imaging used TBI Common Data Elements. Glasgow Outcome Scale-Extended (GOSE) scores were assessed at 2 weeks and 3, 6, and 12 months postinjury. External validation of results was performed via the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. Data analyses were completed from February 2020 to February 2021. Exposures: Acute nonpenetrating head trauma. Main Outcomes and Measures: Frequency, co-occurrence, and clustering of CT features; incomplete recovery (GOSE scores <8 vs 8); and an unfavorable outcome (GOSE scores <5 vs ≥5) at 2 weeks and 3, 6, and 12 months. Results: In 1935 patients with mTBI (mean [SD] age, 41.5 [17.6] years; 1286 men [66.5%]) in the TRACK-TBI cohort and 2594 patients with mTBI (mean [SD] age, 51.8 [20.3] years; 1658 men [63.9%]) in an external validation cohort, hierarchical cluster analysis identified 3 major clusters of CT features: contusion, subarachnoid hemorrhage, and/or subdural hematoma; intraventricular and/or petechial hemorrhage; and epidural hematoma. Contusion, subarachnoid hemorrhage, and/or subdural hematoma features were associated with incomplete recovery (odds ratios [ORs] for GOSE scores <8 at 1 year: TRACK-TBI, 1.80 [95% CI, 1.39-2.33]; CENTER-TBI, 2.73 [95% CI, 2.18-3.41]) and greater degrees of unfavorable outcomes (ORs for GOSE scores <5 at 1 year: TRACK-TBI, 3.23 [95% CI, 1.59-6.58]; CENTER-TBI, 1.68 [95% CI, 1.13-2.49]) out to 12 months after injury, but epidural hematoma was not. Intraventricular and/or petechial hemorrhage was associated with greater degrees of unfavorable outcomes up to 12 months after injury (eg, OR for GOSE scores <5 at 1 year in TRACK-TBI: 3.47 [95% CI, 1.66-7.26]). Some CT features were more strongly associated with outcomes than previously validated variables (eg, ORs for GOSE scores <5 at 1 year in TRACK-TBI: neuropsychiatric history, 1.43 [95% CI.98-2.10] vs contusion, subarachnoid hemorrhage, and/or subdural hematoma, 3.23 [95% CI 1.59-6.58]). Findings were externally validated in 2594 patients with mTBI enrolled in the CENTER-TBI study. Conclusions and Relevance: In this study, pathological CT features carried different prognostic implications after mTBI to 1 year postinjury. Some patterns of injury were associated with worse outcomes than others. These results support that patients with mTBI and these CT features need TBI-specific education and systematic follow-up

Efficient Double Fragmentation ChIP-seq Provides Nucleotide Resolution Protein-DNA Binding Profiles

Immunoprecipitated crosslinked protein-DNA fragments typically range in size from several hundred to several thousand base pairs, with a significant part of chromatin being much longer than the optimal length for next-generation sequencing (NGS) procedures. Because these larger fragments may be non-random and represent relevant biology that may otherwise be missed, but also because they represent a significant fraction of the immunoprecipitated material, we designed a double-fragmentation ChIP-seq procedure. After conventional crosslinking and immunoprecipitation, chromatin is de-crosslinked and sheared a second time to concentrate fragments in the optimal size range for NGS. Besides the benefits of increased chromatin yields, the procedure also eliminates a laborious size-selection step. We show that the double-fragmentation ChIP-seq approach allows for the generation of biologically relevant genome-wide protein-DNA binding profiles from sub-nanogram amounts of TCF7L2/TCF4, TBP and H3K4me3 immunoprecipitated material. Although optimized for the AB/SOLiD platform, the same approach may be applied to other platforms